Protein interaction networks are key determinants of protein function in biological systems. However, global or large-scale analysis of protein interaction networks within native living systems is a challenge that is unmet by today's technology. Improved capabilities to monitor and visualize these networks will have a major impact in the understanding of many diseases including cancer, diabetes, cardiovascular disease and virtually all areas of human health. This project aims to develop enabling technology for improved characterization of protein interaction networks and protein topological features in native cellular environments. This advance is based on the new concepts of a Protein Interaction Reporter (PIR) system that functions by cross-linking proteins in cells and facilitates affinity capture of labeled proteins. The novel, key feature of the PIR system is based on incorporation of a releasable reporter ion that is detected during mass spectrometry analysis. The reporter ions are mass-encoded to facilitate information retrieval from complex cross-linking reaction mixtures that will simultaneously include a wide variety of PIR structures, lengths, physical properties and reactive functionalities. The reporter ions allow product differentiation and protein identification, establish connectivity among cross-linked proteins, and pinpoints sites of protein interactions and exposed protein residues that are present within the cellular environment. The development of functional PIR technology that can enable improved network and topological features to be visualized within cells will significantly improve the ability to understand critical aspects of global protein function relevant to human health.